Autism spectrum disorders (ASD) are complex neurodevelopmental diseases affecting 1 in 150 children in the United States See e.g., MMWR Surveill Summ 56 (1):1-11 (2007). Such diseases are mainly characterized by impaired social interaction and repetitive behavior. Family history and twin studies suggest that, in some cases, these disorders share genetic roots, but the degree to which environmental and genetic patterns account for individual differences within ASD is currently unknown. See e.g., Piven, J. et al., 1997, The American Journal of Psychiatry 154 (2):185-190; Ronald, A. et al., 2006, J Am Acad Child Adolesc Psychiatry 45 (6):691-699. Several reports suggest that many autistic patients have novel genetic alterations, such as SNPs, deletions and duplications in their genomes. See e.g., Sebat, J. et al., 2007, Science 316(5823):445-449; Glessner, J. T. et al., 2009, Nature 459:1461-1465. A different combination of genetic mutations is likely to play a role in each individual. Nevertheless, the study of mutations in specific genes can help to identify molecular mechanisms responsible for subtle alterations in the nervous system, pointing to common mechanisms for ASD.
Rett syndrome (RTT) is a progressive neurological disorder caused by mutations in the X-linked gene encoding MeCP2 protein. See e.g., Amir, R. E. et al. 1999, Nat Genet 23 (2):185-188. RTT patients have a large spectrum of autistic characteristics and are considered part of the ASD population. See e.g., Samaco, R. C. et al., 2004, Hum Mol Genet 13 (6):629-639; Zappella, M. et al., 2003, Am J Med Genet B Neuropsychiatr Genet 119 (1):102-107; Hammer, S. et al., 2002, Ment Retard Dev Disabil Res Rev 8(2):94-98; Samaco, R. C. et al., 2005, Hum Mol Genet 14 (4):483-492. These individuals undergo apparently normal development until 6-18 months of age, followed by impaired motor function, stagnation and then regression of developmental skills, hypotonia, seizures and autistic behavior. See e.g., Amir, R. E. et al, 1999, Id.; Amir, R. E. & Zoghbi, H. Y., 2000, Am J Med Genet 97 (2):147-152. MeCP2 may be involved in the epigenetic regulation of target genes, by binding to methylated CpG dinucleotides within promoters, and may function as a transcriptional repressor, although this view has been challenged recently. See e.g., Yasui, D. H. et al., 2007, Proc Natl Acad Sci USA 104 (49):19416-19421; Chahrour, M. et al., 2008, Science 320 (5880):1224-1229. Without wishing to be bound by any theory, it is believed that genes misregulated by MeCP2 mutations are probably responsible for the phenotypic abnormalities observed rather than the MeCP2 gene itself. However, microarray analyses comparing gene expression in RTT patients or RTT mouse models to wild type (WT) controls have failed to identify many genes with robust changes in gene expression. See, e.g., Traynor, J. et al., 2002, BMC Medical Genetics 3:12; Tudor, M. et al., 2003, Proc Natl Acad Sci USA 99(24):15536-15541. Such subtle gene expression changes will probably target genes expressed only in specific brain regions or neurons that are, therefore, being masked in the analyses of entire brain regions. In support of this argument, a recent study revealed changes in the expression levels of thousands of genes by focusing on mouse hypothalamus only instead of whole brain. See Chahrour, M. et al., 2008, Science 320(5880):1224-1229. It is further believed that such analysis may not determine the affected cell type due to cellular heterogeneity. Furthermore, MeCP2 regulation of target genes is very likely developmental-stage specific. Finally, the majority of the work has been focused on mouse models of RTT or postmortem brain samples, and an in vitro human developmental model of RTT has been lacking.
Pluripotent human embryonic stem cells (hESCs) have been successfully generated from early stage human embryos and can differentiate into various cell types. See, e.g., Thomson, J. A. et al., 1998, Science 282(5391):1145-1147. However, to develop cellular models of human disease, it is necessary to generate cell lines with genomes pre-disposed to diseases. Recently, reprogramming of somatic cells to a pluripotent state by over-expression of specific genes (induced pluripotent stem cells, iPSCs) has been accomplished. See, e.g., Takahashi, K. & Yamanaka, S., 2006, Cell 126(4):663-676; Takahashi, K. et al., 2007, Cell 131 (5):861-872; Yu, J. et al., 2007, Science 318(5858):1917-1920. Resultant iPSCs are isogenic to the donor individual, i.e., they carry the identical genetic background. Isogenic pluripotent cells are attractive not only for their potential therapeutic use with lower risk of immune rejection but also for understanding complex diseases. See, e.g., Marchetto et al., 2010, Cell 143:527-539; Muotri, A. R., 2009, Epilepsy Behav 14:Suppl. 1, 81-85. Although iPSCs have been generated for several neurological diseases (Dimos et al., 2008, Science 321:1218-1221; Ebert et al., 2009, Nature 457:277-280; Hotta et al., 2009, Nat. Methods 6:370-376; Lee et al., 2009, Nature 461:402-406; Park et al., 2008, Cell 134:877-886; Soldner et al., 2009, Cell 136:964-977), the demonstration of disease-specific pathogenesis and phenotypic rescue in relevant cell types is a current challenge in the field (Marchetto et al. 2010, id).
Thus, there is a need in the art for methods and compositions useful in identifying compounds useful in treating a neurological disorder. The present invention addresses these and other needs in the art.